Hydroxycinnamic Acid from Corncob and Its Structural Analogues Inhibit Aβ40 Fibrillation and Attenuate Aβ40-Induced Cytotoxicity

Abstract

The aggregation of amyloid-β protein (Aβ) is deemed a vital pathological feature of Alzheimer's disease (AD). Hence, inhibiting Aβ aggregation is noticed as a major tactic for the prevention and therapy of AD. Hydroxycinnamic acid, as a natural phenolic compound, is widely present in plant foods and has several biological activities including anti-inflammation, antioxidation, and neuroprotective effects. Here, it was found that hydroxycinnamic acid and its structural analogues (3hydroxycinnamic acid, 2-hydroxycinnamic acid, cinnamic acid, 3,4-dihydroxycinnamic acid, 2,4-dihydroxycinnamic acid, and 3,4,5trihydroxycinnamic acid) could inhibit Aβ40 fibrillogenesis and reduce Aβ40-induced cytotoxicity in a dose-dependent manner. Among these small molecules investigated, 3,4,5-trihydroxycinnamic acid is considered to be the most effective inhibitor, which reduces the ThT fluorescence intensity to 30.79% and increases cell viability from 49.47 to 84.78% at 200 μM. Also, the results with Caenorhabditis elegans verified that these small molecules can ameliorate AD-like symptoms of worm paralysis. Moreover, molecular docking studies showed that these small molecules interact with the Aβ40 mainly via hydrogen bonding. These results suggest that hydroxycinnamic acid and its structural analogues could inhibit Aβ40 fibrillogenesis and the inhibition activity is enhanced with the increase of phenolic hydroxyl groups of inhibitors. These small molecules have huge potential to be developed into novel aggregation inhibitors in neurodegenerative disorders.

Overview of Beneficial Effects of (Poly)phenol Metabolites in the Context of Neurodegenerative Diseases on Model Organisms

“…Cinnamic acids described as LMWPM, 3-hydroxycinnamic acid, 2hydroxycinnamic acid, cinnamic acid, 3,4-dihydroxycinnamic acid, 2,4-dihydroxycinnamic acid, and 3,4,5-trihydroxycinnamic acid were shown to inhibit Aβ 40 fibrillogenesis and reduced Aβ 40 -induced cytotoxicity in a dose-dependent manner in cells, demonstrating the potential of cinnamic acids and the need to test other LMWPM. When hydroxycinnamic acid was given to a C. elegans transgenic line, CL4176, which expresses human Aβ in muscle and gives rise to a paralysis phenotype in the worms due to the generation of Aβ deposits, the results showed that all small molecules delayed the progress of Aβ-induced paralysis in a dose-dependent manner [101]. [32], however the name cited in the original publications where the effect is described is indicated in brackets.…”

“…Treatment of C. elegans with cinnamic acid has also been performed. In particular, administration of hydroxycinnamic acid [ 101 ], 3,4—dihydroxycinnamic acid [ 102 , 103 ], 4—hydroxy–3—methoxycinnamic acid [ 104 ] and 3–(3′,4′—dihydroxyphenyl)propanoic acid [ 103 ] have been shown to give promising results regarding the neuroprotective potential of these compounds. Cinnamic acids described as LMWPM, 3—hydroxycinnamic acid, 2—hydroxycinnamic acid, cinnamic acid, 3,4—dihydroxycinnamic acid, 2,4—dihydroxycinnamic acid, and 3,4,5—trihydroxycinnamic acid were shown to inhibit Aβ 40 fibrillogenesis and reduced Aβ 40 —induced cytotoxicity in a dose—dependent manner in cells, demonstrating the potential of cinnamic acids and the need to test other LMWPM.…”

Glycosides and Their Corresponding Small Molecules Inhibit Aggregation and Alleviate Cytotoxicity of Aβ40

“…In Aβ40 aggregation (in Figure 2B), after Aβ40 was incubated for 24 h, it caused visible cytotoxicity, and cell viability was dropped to 46.67%, which was consistent with our previous study. 37 By comparison, when different concentrations of glycosides and their corresponding small molecules were mixed in the Aβ40 solution, these inhibitors all saved PC 12 cells from Aβ40induced apoptosis to an obvious extent. Notably, glycosides exhibited better cell protection activity than their corresponding small molecules (the molar ratio of Aβ40: inhibitors were 1:4, 1:1, and 1:0.25, and the corresponding concentrations were 160, 40, and 10 μM), and the protection was in a dosedependent mode.…”

The Use of Bioactive Compounds in Hyperglycemia- and Amyloid Fibrils-Induced Toxicity in Type 2 Diabetes and Alzheimer’s Disease

“…When examining the bioactivity of p-HCA in the brain, in vitro study on primary cortical neurons revealed that p-CA has a potent inhibitory effect against 5-S-cysteinyl-dopamine induced neurotoxicity and thus, counteracts the progression of neurological disorders [101]. The neuroprotective activity of p-CA was also confirmed in pheochromocytoma PC12 cells where it suppressed formation of ROS [102], attenuated beta amyloid-induced apoptosis [103,104], and inhibited expression of inflammatory target proteins via inactivation of NF-κB and MAPKs signaling pathways [105]. Recent in vivo and in vitro experiments showed that p-CA promoted neural stem cell proliferation via activation of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/AKT signaling pathway, improved spatial learning and memory functions, and reduced anxiety in post-ischemic stroke rats [106].…”